Weight gain is a growing problem in the world population, especially in North America and Europe. Excess body weight, particularly in abdominal fat, is associated with a number of comorbidities including a significantly elevated risk for type 2 diabetes, coronary heart disease, stroke, hypertension, various types of cancer and numerous other major illnesses, and overall mortality from all causes (Must et al, 1999, JAMA 282:1523-1529, Calle et al, 1999, N. Engl. J. Med. 341:1097-1 105).
Existing therapies for the treatment and/or prevention of weight gain include for example GLP-1 agonists and central neurotransmitter modulators such as Contrave or Lorcaserin. However, these medicines generally elicit modest weight loss (3-8% after one year of treatment) and are associated with safety concerns including pancreatitis and cardiovascular effects (GLP-1 agonists) and changes in mood and/or cognition for the neurotransmitter modulators.
Non-medicinal therapies include standard diets and exercise, very low calorie diets, behavioral therapy, pharmacotherapy involving appetite suppressants, thermogenic drugs, food absorption inhibitors, mechanical devices such as jaw wiring, waist cords and balloons, and gastric bypass surgery. However, these non-medicinal therapies, although widely used are not very effective. Adherence to energy restriction diets is problematic and generally unsuccessful and the efficacy of gastric bypass surgery tends to wane over time with regard to long-term weight management.
The development of novel medicines for the treatment of excess body weight have often been limited by toxicity and side effects including tachycardia (increased heart rate), pulmonary hypertension, heart valve damage, and drug dependency (addiction).
Therefore, there remains a need for new products useful for treating and/or preventing excess body fat and/or of excess body weight.
Localized fat accumulations may also occur in a non-pathological manner (i.e. non-associated with an increased burden of disease) in individuals being in good health with a normal corpulence, according to the WHO standards. Such fat accumulation, although not directly affecting the health, may be considered as being unaesthetic. Therefore, it is also useful to develop cosmetic methods to allow people who are in good health to stabilize weight and to stay thin without localized fat deposits.
Such therapeutic or cosmetic strategies will be all the more useful as they will make it possible to preferably target body fat loss while preserving the lean body mass.
Surprisingly, the Applicant have found that the selective antagonism of the neurokinin-3 receptor (NK3R), is beneficial in weight control, specifically with regard to a reduction in body fat. The NK3 receptor is a target known to modulate the hypothalamic-pituitary-gonadal axis (HPG axis), which is of relevance to body metabolism. The Applicant also evidenced that the use of NK3R antagonists increases circulating leptin levels, which may explain the observed effect on weight and body fat. Indeed, leptin is known to be the “satiety hormone” which enables to achieve energy homeostasis and which able to trigger impressive weight loss in some patient.
The present invention is all the more surprising that inhibition or negative modulation of other targets known to modulate the HPG axis similarly to NK3 receptor is conversely reported to lead to an increase in weight gain. This was especially shown for the GnRH receptor (Ozono et al., 2012, Jpn J Clin Oncol 42:477-84; Tascilar et al., 2011, Turk J Pediatrics) and for the Kisspeptin (GPR54) receptor (Tolson et al., 2014; J Clin Invest 124:3075-3079).
Besides, a study showed that NK3-knockout mice underwent weight increase (Siociak et al., Psychopharmacology, 2007, 197, 185-195). This result is not contradictory with the findings of the present invention since the genetic deletion of the NK3 receptor cannot be assimilated to the pharmacological inhibition of a receptor activity by an NK3R antagonist, since genetic deletion of a receptor induces a lot of other changes.
Another study was conducted on rats fed with a standard chow diet or fed with a high-fat diet to which SB222200 NK3R antagonist was administered (Li et al., J. Neuroendocrinology, 2014, 26, 521-527). In this study, no effect on weight was observed. SB222200 NK3R antagonist is known to have a non-optimal pharmacological profile, which, may explain the absence of effects on weight observed in rats for SB222200.
Moreover, the present invention is all the more surprising that despite the previous drug development and clinical testing of various NK3R antagonists, it was never previously disclosed that NK3R antagonists may be beneficial in weight control, specifically with regards of reduction of body fat and so prevention of body fat gain.
The current invention demonstrates for the first time that the use of an NK3R antagonist prevents adiposity-induced weight gain. It is also evidenced that the use of an NK3R antagonist enables weight loss by reduction of fat mass, without substantial muscle loss.